Project Summary Urologic chronic pelvic pain (UCPP) syndromes are the most common chronic visceral pain conditions, affecting between 5 and 10 million people in the United States. The lack of effective treatments for UCPP is likely due, in part, to a failure to understand the central nervous system's contribution to the modulation of the disease. Recent evidence has implicated the central nucleus of the amygdala as an important region in the pathology of bladder pain. Evidence from both human and rodent models indicates that the left and right amygdala have different contributions to the modulation of pain. UCPP patients exhibit lateralized changes in amygdala functional connectivity compared to healthy patients and patients suffering from other visceral pain conditions. Recently, the right and left central amygdala has been shown to have divergent functions in the context of bladder pain in mice. We aim to further explore this lateralization in order to determine molecular modulators responsible for driving these differential functions. Calcitonin gene related peptide (CGRP) is a neuropeptide that separately has been shown to have both pro- and anti-nociceptive functions in the central amygdala. Our preliminary data indicates that CGRP activity shows interesting asymmetries in the context of bladder pain, with CGRP in the right central amygdala driving bladder pain but CGRP in the left central amygdala blocking bladder pain. The goal of this proposal is to understand how CGRP contributes to the differential modulation of bladder pain in the left and/or right central amygdala. We will approach this goal by 1) exploring the influence of brainstem CGRP-expressing projections in the central amygdala on the physiological response to bladder stimulation and 2) investigating the contribution of these same CGRP cells on the modulation of pain-like behavior in awake animals using a mouse model of inflammatory bladder pain. These experiments will not only help determine the extent of CGRP in the differential processing of bladder pain by the left and right central amygdala but also provide a better understanding of a contributing mechanism to UCPP and therefore open the door for more advanced and effective CNS targeted therapies for patients.